Using urazole analogs of prostaglandins for bronchodilation

ABSTRACT

Compounds of the formula (I) ##STR1## wherein; n is 1 to 5 
     Y is --CH 2  --CH 2  or --CH═CH--; 
     R 1  is hydrogen or CO 2  R 1  represents an ester group in which the R 1  moiety contains from 1-12 carbon atoms; 
     R 2  is hydrogen, C 1-4  alkyl, or phenyl; 
     R 3  is hydroxy or protected hydroxy; 
     R 4  is hydrogen, C 1-9  alkyl, C 3-8  cycloalkyl, C 3-8  cycloalkyl-C 1-6  alkyl, phenyl, phenyl -C 1-6  alkyl, naphthyl, naphthyl C 1-6  alkyl, any of which phenyl moieties or naphthyl moieties may be substituted by one or more halogen trifluoromethyl, C 1-6  alkyl, hydroxy, C 1-6  alkoxy, phenyl C 1-6  alkoxy or nitro groups; 
     R 5  is hydrogen, C 1-6  alkyl, C 5-8  cycloalkyl, phenyl, phenyl-C 1-6  alkyl or phenyl C 3-6  cycloalkyl, any of which phenyl moieties may be substituted by one or more halogen, trifluoromethyl, C 1-6  alkyl, C 1-6  alkoxy or nitro groups; or 
     R 2  and R 4  taken with the carbon atom to which they are joined represent a C 5-8  cycloalkyl group; and salts thereof are useful for their prostaglandin-like activity.

CROSS-REFERENCE

This is a continuation, of Ser. No. 858,554, filed Dec. 8, 1977, now U.S. Pat. No. 4,367,338 issued Jan. 4, 1983.

This invention relates to novel compounds having pharmacological activity, to a process for their preparation, to intermediates useful in that process and to pharmaceutical compositions containing them.

Offenlegungsschrift No: 2323193 discloses that pyrazolidine derivatives of the formula (I)': ##STR2## wherein; A is CH═CH or C.tbd.C; R is H, an alkali metal, an amine salt, or an γ 12C hydrocarbon or chlorohydrocarbon residue; m is 0 or 1; n is 0-6; p is 0-6; and Y and Z are O or H except that Y and Z are not both 0; have similar biological properties to the prostaglandins or are antagonists of prostaglandins.

French Patent Application No: 2258376 discloses that 10-aza prostaglandins of formula (II)": ##STR3## wherein; R═H or lower alkyl; R' and R"═CH₃ or C₂ H₅ ; R°=H or lower alkyl; Y=--CH₂ --CH₂ --, or --CH═CH--; Z=--CO or --CH(˜OH)--; are useful in the treatment of blood pressure and gastro-intestinal disorders, and in the preparation for confinement.

Belgian Pat. No: 835989 discloses that compounds of the formula (III)": ##STR4## wherein: X is CO, protected CO, CROH in which R is hydrogen or C₁₋₄ alkyl and in which the OH moiety may be protected; Y is CH₂ CH₂ or CH═CH; Z is CO or CH₂ ; n is 1 to 8; m is 1, 2 or 3; R₁ is hydrogen, CH₂ OH, CH₂ OH in which the OH moiety is protected, CO₂ W wherein W is hydrogen or CO₂ W represents an ester group in which the ester moiety contains from 1 to 12 carbon atoms, or CONH₂ ; R₂ is hydrogen, C₁₋₄ alkyl, or taken together with R₃ and the carbon atom to which it is attached represents a carbonyl group; R₃ is hydrogen, hydroxy or protected hydroxy; R₄ is hydrogen or C₁₋₉ alkyl; and salts thereof; have useful pharmacological activity.

A novel class of compounds also having useful pharmacological activity has now been discovered, which compounds are structurally distinct from the prior art referred to above. Accordingly the present invention provides a compound of the formula (I); ##STR5## wherein;

n is 1 to 5

Y is --CH₂ --CH₂ -- or --CH═CH--;

R₁ is hydrogen or CO₂ R₁ represents an ester group in which the R₁ moiety contains from 1-12 carbon atoms;

R₂ is hydrogen, C₁₋₄ alkyl, or phenyl;

R₃ is hydroxy or protected hydroxy;

R₄ is hydrogen, C₁₋₉ alkyl, C₃₋₈ cycloalkyl, C₃₋₈ cycloalkyl-C₁₋₆ alkyl, phenyl, phenyl --C₁₋₆ alkyl, naphthyl, naphthyl C₁₋₆ alkyl, any of which phenyl moieties or naphthyl moieties may be substituted by one or more halogen, trifluoromethyl, C₁₋₆ alkyl, hydroxy, C₁₋₆ alkoxy, phenyl C₁₋₆ alkoxy or nitro groups;

R₅ is hydrogen, C₁₋₆ alkyl, C₅₋₈ cycloalkyl, phenyl, phenyl-C₁₋₆ alkyl or phenyl C₃₋₆ cycloalkyl, any of which phenyl moieties may be substituted by one or more halogen, trifluoromethyl, C₁₋₆ alkyl, C₁₋₆ alkoxy or nitro groups; or

R₂ and R₄ taken with the carbon atom to which they are joined represent a C₅₋₈ cycloalkyl group; and salts thereof.

A group of compounds within formula (I) include those wherein:

n is 1 to 5;

Y is --CH₂ --CH₂ or --CH═CH--;

R₁ is hydrogen or CO₂ R₁ represents an ester group in which the R₁ moiety contains from 1 to 12 carbon atoms;

R₂ is hydrogen, C₁₋₄ alkyl, or phenyl;

R₃ is hydroxy or protected hydroxy;

R₄ is hydrogen, C₁₋₉ alkyl, C₅₋₈ cycloalkyl, C₅₋₈ cycloalkyl-C₁₋₆ alkyl, phenyl, phenyl-C₁₋₆ alkyl, naphthyl, naphthyl C₁₋₆ alkyl, any of which phenyl or naphthyl moieties may be substituted by one or more halogen, trifluoromethyl, C₁₋₆ alkyl, C₁₋₆ alkoxy or nitro groups;

R₅ is hydrogen, C₁₋₆ alkyl, phenyl or phenyl-C₁₋₆ alkyl; and salts thereof.

Suitably n is 2, 3 or 4, preferably 3. Similarly Y may be --CH₂ --CH₂ -- or --CH═CH--, suitably --CH₂ --CH₂ --.

R₁ is hydrogen or CO₂ R₁ represents an ester group in which the R₁ moiety contains from 1 to 12 carbon atoms. Examples of R₁ include hydrogen, methyl, ethyl, n- and iso-propyl, n-, sec- and tert-butyl, phenyl, benzyl, toluyl and the like, while normally hydrogen or C₁₋₆ alkyl groups are preferred.

Suitable examples of R₂ include hydrogen; methyl, ethyl; and phenyl. Preferred examples of R₂ include hydrogen.

Suitable protected hydroxy groups R₃ include readily hydrolysable derivatives such as acylated hydroxy groups in which the acyl moiety contains 1 to 4 carbon atoms, for example the acetoxy group; and hydroxy groups etherified by readily removable inert groups such as the benzyl or like groups. Preferably however R₃ is hydroxy.

Suitable groups R₄ when R₄ is an alkyl group include C₄₋₉ alkyl groups. Such C₄₋₉ alkyl groups may be straight chain alkyl groups, such as n-butyl, n-pentyl, n-hexyl and n-heptyl, or may be alkyl groups branched by one or two methyl groups (at the same or different carbon atoms). Thus for example, R₄ may be a group CH₂ R₆, CH(CH₃)R₆ or C(CH₃)₂ R₆, wherein R₆ is a straight chain alkyl group such that the carbon content of the resultant group R₄ is 4 to 9.

In general preferred groups R₄ when R₄ is an alkyl group include straight chain pentyl, hexyl and heptyl groups. Other preferred groups R₄ include groups CH(CH₃)R₆ and C(CH₃)₂ R₆ wherein R₆ is straight chain butyl, pentyl and hexyl.

When R₄ is or contains a C₃₋₈ cycloalkyl moiety, the moiety may suitably be a C₅₋₈ cycloalkyl moiety such as a cyclohexyl moiety. It may be a cyclopropyl moiety. Examples of suitable C₁₋₆ alkyl moieties when R₄ is a cycloalkyl-C₁₋₆ alkyl group include methyl, ethyl, propyl, butyl and amyl.

When R₂ and R₄ together with the carbon atom to which they are joined represent a C₅₋₈ cycloalkyl group, they suitably represent cyclohexyl.

When R₄ is an aryl group as previously defined, suitable groups R₄ include phenyl, phenylmethyl, phenylethyl, phenyl n-propyl, phenyl-n-butyl, naphthyl, naphthylmethyl, naphthylethyl, naphthyl n-propyl and naphthyl n-butyl, and such groups branched in the alkyl moiety by one or two methyl groups (at the same or different carbon atoms). These groups may be substituted in the phenyl or naphthyl moiety by normally one, two or three groups selected from those substituent groups listed hereinbefore. Examples of suitable substituent groups include fluorine, chlorine and bromine atoms and CF₃, methyl, ethyl n- and iso-propyl, methoxy, ethoxy, n- and iso-propoxy and nitro groups. Other examples of such groups include hydroxy and benzyloxy. Preferably the aryl moieties when substituted by such groups will be mono- or di-substituted.

Suitable examples of R₅ include hydrogen; methyl, ethyl, n- and iso-propyl, and n-, sec- and tert-butyl; phenyl; phenylmethyl, phenylethyl, phenyl-n-propyl and phenyl-n-butyl, and such groups branched in the alkyl moiety by one or two methyl groups (at the same or different carbon atoms). Preferred R₅ groups include C₁₋₆ alkyl.

Other examples of R₅ include cyclohexyl; and the aforementioned R₅ phenyl containing groups in which the phenyl moieties are substituted as for R₄ aryl groups.

R₅ may also be a phenyl-C₃₋₆ cycloalkyl group, in which case suitable examples of R₅ include phenyl-cyclopropyl.

The compounds of the formula (I) may form conventional salts when R₁ is hydrogen and also when R₅ is hydrogen.

Such salts include those with alkali and alkaline earth metals, suitably sodium and potassium, and ammonium and substituted ammonium salts.

Normally salts of the R₅ hydrogen will be with alkali metals. One particularly suitable sub-group of compounds within formula (I) is of formula (II): ##STR6## wherein:

Y, R₁ and R₅ are as defined in formula (I);

n¹ is 2, 3 or 4;

R¹ ₂ is hydrogen, methyl, ethyl or phenyl;

R¹ ₄ is hydrogen or C₁₋₉ alkyl; and salts thereof.

Suitably in formula (II) n¹ is 3.

Suitably R₁ is hydrogen or C₁₋₆ alkyl, preferably hydrogen.

Suitably R¹ ₂ is hydrogen, methyl or ethyl.

While R₄ may be hydrogen or a C₁₋₉ alkyl group in formula (II), it is normally a C₄₋₉ alkyl group. In such cases suitable and preferred straight chain and branched groups R¹ ₄ include those previously described as suitable and preferred for the group R₄ when R₄ is a C₄₋₉ alkyl group. Such preferred groups R¹ ₄ include straight chain pentyl, hexyl and heptyl. Other preferred groups R¹ ₄ include CH(CH₃)R¹ ₆ and C(CH₃)₂ R¹ ₆ wherein R¹ ₆ is straight chain butyl, pentyl or hexyl.

Often in formula (II) R₅ will be a C₁₋₆ alkyl, phenyl or phenyl C₁₋₆ alkyl group, or hydrogen.

Preferably R₅ is a C₁₋₆ alkyl group.

From the aforesaid it will be realised that one preferred group within formula (II) is of formula (III): ##STR7## wherein:

R¹ is as defined in formula (I);

R¹ ₂ is hydrogen, methyl or ethyl;

R² ₄ is a C₄₋₉ alkyl group;

R¹ ₅ is a C₁₋₆ alkyl group: and salts thereof.

Suitably R₁ in formula(III) is hydrogen or C₁₋₆ alkyl, preferably hydrogen. Suitable and preferred groups R² ₄ include those listed hereinbefore for R¹ ₄ when R¹ ₄ is a C₄₋₉ alkyl group.

Preferred groups R¹ ₅ include methyl.

Another particularly suitable sub-group of compounds within formula (I) is of formula (IV): ##STR8## wherein:

Y, R₁, and R₅ are as defined in formula (I);

n¹ is 2, 3 or 4;

R¹ ₂ is hydrogen, methyl, ethyl or phenyl;

R³ ₄ is a group of formula (V): ##STR9## wherein; T is a bond, or a C₁₋₆ alkylene group which may be straight chain or branched by one or two methyl groups at the same or different carbon atoms; and V, W and Z are each hydrogen or fluorine, chlorine or bromine atoms, or CF₃, methyl, ethyl, n- or iso-propyl, methoxy, ethoxy, n or iso-propoxy or nitro groups; and salts thereof.

In formula (IV) it is preferred that n¹ is 3.

Suitably R₁ is hydrogen or C₁₋₆ alkyl, more preferably hydrogen.

In formula (V) it is often preferred that T is a group --(CH₂)_(q) -- wherein q is 0 to 4. Also V and W will often be hydrogen.

Often in formula (II) R₅ will be a C₁₋₆ alkyl, phenyl or phenyl C₁₋₆ alkyl group, or hydrogen.

Preferably R₅ is a C₁₋₆ alkyl group, such as methyl.

A further sub-group of compounds within the formula (I) is of formula (VI): ##STR10## wherein the variable groups are as defined in formula (II) and R⁴ ₄ is a group of formula (VII): ##STR11## wherein T is as defined in formula (V) and r is 0-3.

Suitable and preferred variable groups in formula (VI) are as in formula (II).

T will often be a group --(CH₂)_(q) -- wherein q is 0 to 4. Also suitably r is 1.

One compound of the invention that is particularly preferred for its useful activity is compound 32 of Table 6 of the Examples.

The invention also provides a process for the preparation of a compound of the formula (I), which process comprises reacting a compound of formula (IX): ##STR12## wherein; R₂, R₃, R₄ and R₅ are as defined in formula (I), with a compound of formula (X):

    Z--CH.sub.2 --Y--(CH.sub.2).sub.n CO.sub.2 R.sub.1

wherein Z is a good leaving group, and Y, n and R₁ are as defined in formula (I).

Z is suitably a halogen, such as bromine, and the reaction suitably carried out in an organic solvent such as hexamethylphosphoramide or the like in the presence of a base such as sodium carbonate or the like. Generally it is preferred that R₁ in the compound of formula (X) is other than hydrogen, and so if in this case a R₁ hydrogen compound of the formula (I) is desired it is prepared from the thus formed compound of the formula (I) by a conventional de-esterification reaction. When R₃ is a protected hydroxy group in the compound of formula (IX), then if in this case a compound of the formula (I) wherein R₃ is hydroxy is required it is prepared from the thus formed R₃ protected hydroxy compound by conventional de-protection reactions. For example, when R₃ is a benzyloxy group, the benzyl group may readily be removed by hydrogenolysis. Thus it can be seen that compounds of the formula (I) wherein R₃ is protected hydroxy are useful intermediates in the preparation of the corresponding free hydroxy compounds of the formula (I).

The invention also provides a preferred process for the preparation of a compound of the formula (I), which process comprises reacting a compound of the formula (XI): ##STR13## wherein; Y, n, R₁, R₄ and R₅ are as defined in formula (I); with a reducing agent to give a corresponding compound of the formula (I) wherein R₂ is hydrogen and R₃ is hydroxy, or with a C₁₋₄ alkyl or phenyl Grignard reagent or C₁₋₄ alkyl or phenyl metallic complex to give a corresponding compound of the formula (I) wherein; R₂ is C₁₋₄ alkyl or phenyl, and R₃ is hydroxy; and then optionally protecting the R₃ hydroxy moiety.

The reduction of the side chain carbonyl in a compound of the formula (XI) may be carried out by conventional methods for reducing a ketone to an alcohol, for example by sodium borohydride reduction.

The C₁₋₄ alkyl or phenyl Grignard reagent or C₁₋₄ alkyl or phenyl metallic (suitably C₁₋₄ alkyl or phenyl lithium) complex reaction may be carried out under conventional conditions for such reactions, for example in an inert anhydrous solvent.

The optional protection of the R₃ hydroxy moiety may be carried out in conventional manner, for example by acylating, alkylating or benzylating the R₃ hydroxy compound.

After these reactions if so desired the group R₁ in the thus formed compounds of the formula (I) may be varied by conventional esterification and/or de-esterification reactions. Similarly when R₁ and/or R₅ is hydrogen in such compounds of the formula (I), salts of these compounds may be prepared in conventional manner, for example, by reacting the chosen compound of the formula (I) with the required base. Preferably strong bases such as sodium in an alcohol, e.g. ethanol, and similar reagents are used to obtain salts of R₅ ═H compounds.

The preparation of the intermediates for use in the processes of the invention will now be described.

Compounds of the formula (IX) may be prepared by reacting a compound of the formula (XII): ##STR14## with a reducing agent to give a corresponding compound of the formula (IX) wherein R₂ is hydrogen and R₃ is hydroxy; or by reacting a compound of formula (XIII) as hereinafter defined with a compound of formula (XVI) as hereinafter defined.

The reduction may be carried out as hereinbefore described with reference to compounds of the formula (XI). The reaction of a compound of formula (XIII) with a compound of formula (XVI) may suitably be carried out as described.

Compounds of the formula (X) are either known compounds or may be prepared by a process analogous to those used for preparing known compounds.

Compounds of the formula (XI) may be prepared by a process which comprises reacting a compound of the formula (XII) as defined with a compound of the formula (X) as defined.

Compounds of the formula (XII) may be prepared by reacting a compound of formula (XIII): ##STR15## with a strong base and a compound of formula (XIV): ##STR16##

Compounds of the formula (XIII) are either known compounds or can be prepared in analogous manner to known compounds. For example in our hands, one suitable reaction scheme for the preparation of these compounds is shown below: ##STR17##

The invention also provides a further preferred process for the preparation of a compound of the formula (I), which process comprises reacting a compound of formula (XV): ##STR18## wherein; Y, n, R₁ and R₅ are as defined in formula (I), with a compound of formula (XVI): ##STR19## wherein D is a good leaving group, and R₂, R₃ and R₄ are as defined in formula (I).

This reaction is suitably carried out in an inert organic solvent, such as hexamethylphosphoramide or N,N-dimethylformamide, at room temperature, in the presence of a base, such as sodium carbonate or sodium hydride, and a source of alkali metal ions, such as an alkali metal halide. Suitable alkali halides include sodium iodide and lithium iodide.

Suitable examples of D include tosylate, bromide or iodide.

Preferably D is a tosylate residue.

The compound of formula (XV) may be prepared by reacting a compound of formula (XVII): ##STR20## with a compound of formula and then if necessary reducing the resulting Y is CH═CH compound to the corresponding Y is CH₂ CH₂ compound.

This reaction is suitably carried out in an inert organic solvent, such as benzene, at the reflux temperature, under an inert atmosphere. It should be mentioned that to prepare a compound of the formula (XV) wherein R₁ is other than hydrogen, it is generally preferred to prepare the corresponding compound of the formula (XV) wherein R₁ is hydrogen and then toconvert that compound to the desired compound by conventional methods. For example a R₁ is hydrogen compound may be converted to a R₁ is methyl compound by treatment with acetyl chloride in methanol.

The optical reduction can be carried out in conventional manner.

The compound of formula (XVII) may be prepared by treating a compound of formula (XIII) as hereinbefore defined, that is, a compound of formula: ##STR21## with an oxidising agent, such as N₂ O₄ or t-butyl hypochlorite.

This reaction is suitably carried out by suspending the chosen compound of the formula (XIII) in an inert organic solvent, such as dichloromethane, at 0° C., and bubbling N₂ O₄ through this suspension, or adding a known volume of N₂ O₄ in dichloromethane slowly to the suspension.

The preparation of the compounds of the formula (XIII) has been discussed hereinbefore.

It is believed that compounds of formula (IX), (XI), (XII) and (XV) are novel compounds, and these compounds are useful intermediates as hereinbefore described. As such, they from an important part of this invention.

It will be realised by the skilled reader that although the reaction sequences leading to the active compounds of the invention hereinbefore described are particularly suitable, a number of variations in the sequences are possible. It is believed these variations are best illustrated by use of the following flow diagram.

(The reactions represented by arrows in the flow diagram are carried out as hereinbefore described, or in an analogous manner). ##STR22##

It will of course be realised that the compounds of the formula (I) have an asymmetric centre, and thus are capable of existing in two enantiomeric forms. The invention extends to each of these isomeric forms, and to mixtures thereof. The different isomeric forms may be resolved by the usual methods.

Compounds within the formula (I) have useful pharmacological activity. For examples compounds within the formula (I) have anti-gastric secretion activity e.g. anti-ulcer activity, cardiovascular activity, e.g. anti-hypertensive activity or anti-arrhythmic activity, platelet aggregation inhibition activity, affect the respiratory tract e.g. bronchodilator activity, and have anti-fertility and smooth muscle activity.

In general it may be said that compounds within the formula (I) have a range of pharmacological activities similar to those shown by the natural prostaglandins, but that these activities tend to be rather more selective.

The invention therefore also provides a pharmaceutical composition comprising a compound of the formula (I) and a pharmaceutically acceptable carrier.

Clearly the formulation of the said pharmaceutical composition will depend on the nature of the activity shown by the chosen compound of the formula (I), and on other factors such as a preference in a particular area of therapy for a particular mode of administration.

The compositions may be in the form of tablets, capsules, powders, granules, lozenges or liquid preparations, such as oral or sterile parenteral solutions or suspensions.

Tablets and capsules for oral administration may be in unit dose presentation from, and may contain conventional excipients such as binding agents, fillers, tabletting lubricants, disintegrants, and acceptable wetting agents and the like. The tablets may be coated according to methods well known in normal pharmaceutical practice. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, nonaqueous vehicles (which may include edible oils), preservatives, and if desired conventional flavouring or colouring agents, and the like.

For parenteral administration, fluid unit dosage forms are prepared utilizing the compound of the formula (I) and a sterile vehicle. The compound, depending on concentration used, can be either suspended or dissolved in the vehicle. In preparing solutions the compound can be dissolved for injection and filter sterilized before filling into a suitable vial or ampoule and sealing. Advantageously, adjuvants such as a local anaesthetic, preservatives and buffering agents can be dissolved in the vehicle. Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilization cannot be accomplished by filtration. The compound can be sterilized by exposure to ethylene oxide before suspending in the sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.

When appropriate, the compositions of this invention may be presented as an aerosol for oral administration, or as a microfine powder for insufflation.

As is common practice, the compositions will usually be accompanied by written or printed directions for use in the medical treatment concerned.

It will of course be realised that the precise dosage used in the treatment of any of the hereinbefore described disorders will depend on the actual compound of the formula (I) used, and also on other factors such as the seriousness of the disorder being treated.

The invention also provides a method of treatment and/or prophylaxis of disorders in human beings which comprises the administration to the sufferer or an effective amount of a compound of the formula(I).

Animals may also be heated with the compounds of the invention.

Examples 1 to 9 illustrate the preparation of the active compounds of the invention by the (XIII)→(XII)→(XI)→(I) route, as illustrated in the flow diagram.

EXAMPLE 1 Preparation of ethyl-N-tricarboxylate

Ref. Org. Syn. Coll. Vol.III, p. 415, C. F. H. Allen and Alan Bell.

Sodium (44 g, 1.93 g atom) was cut into small pieces and added to a solution of urethane (90 g, 1.01 mol) in dry ether (1.5 l) [the urethane was dried overnight in vacuo over KOH]. The mixture was stirred for 2 hours, then boiled at reflux for 3 hours and then cooled in ice-water. Ethyl chloroformate (210 g, 1.95 mol) was then added dropwise over 2 hours and the resultant mixture stirred overnight at room temperature and then filtered. The residue was washed with ether (2×200 ml) and the ether was removed from the filtrate by evaporation in vacuo. The residual oil was distilled b.p. 118-128/6 mm. Yield 86 g.

EXAMPLE 2 Preparation of ethyl carbazate

C. F. H. Allen and Alan Bell. Org. Syn. Coll. Vol. III, p. 404.

To ethyl-N-tricarboxylate (86 g, 0.37 mol) stirred and cooled in an ice-bath was added slowly hydrazine hydrate (50 g, 1.0 mol). After complete addition the mixture was heated on a water bath for 0.5 hr and to the reaction mixture ethanol (100 ml) was added. This mixture was heated on the water bath (with stirring) for a further 2 hr and then cooled and filtered. The residue was washed with ethanol and the filtrate evaporated in vacuo to give an oil to which more ethanol was added and the solution was allowed to stand overnight at room temperature. The resultant mixture was refiltered, the ethanol was removed from the filtrate in vacuo and the residual oil distilled, b.p. 64°-66°/3 mm. Yield 68 g. This distillate was re-distilled, b.p. 92°-95°/15 mm. Yield 60 g.

EXAMPLE 3 4-Methyl-1,2,4-triazolidone-3,5-dione (Compound 2)

G. Zimmer and W. Deucker. Arch. Pharm., 1961, 294, 370 C. A. 1961, 55, 22298.

Ethyl carbazate (12.0 g, 0.115 mol) in dry benzene (60 ml) was treated dropwise with methyl isocyanate (6.5 ml, 6.0 g, 0.105 mol) and after complete addition the mixture was boiled at reflux for 20 min. This solution was allowed to cool and then 4N aqueous potassium hydroxide (50 ml) was added and the resultant mixture heated at ca. 40° C. for 20 min. This solution was then cooled and acidified with concentrated hydrochloric acid and then evaporated in vacuo to give a white solid. This solid was boiled at reflux in ethanol (300 ml) for 2 hr and the resultant mixture filtered while hot. The filtrate was allowed to cool and refiltered, this filtrate was evaporated to dryness to afford 4-methyl urazole (10.5 g), m.p. 222°-4°. The compounds in Table 1 were prepared in similar manner.

                  TABLE 1                                                          ______________________________________                                          ##STR23##                                                                       Compound           R.sub.5                                                                               m.p.                                               ______________________________________                                         1               Ph      204-6°                                          2               Me      222-4°                                          3               Et      184-6°                                          ______________________________________                                          R.sub.5 = H (4), available commercially                                  

EXAMPLE 4 4-Methyl-2-(3'-oxo-octyl)-1,2,4-triazolidine-3,5-dione (Compound 7)

To a solution of 4-methyl-1,2,4-triazolidine-3,5-dione (5.75 g, 0.05 mol) in dry dimethylformamide (40 ml) stirred at 75° under a nitrogen atmosphere was added portionwise sodium hydride (1.575 g, 0.055 mol, as an 80% dispersion in mineral oil) and the resultant solution stirred at 75° for 0.5 hr. To this solution was added oct-1-en-3-one (6.57 g, 0.055 mol) dropwise in dimethylformamide (20 ml) and the solution heated with stirring for 48 hr at 75°. The reaction mixture was then cooled, taken up in ethyl acetate (100 ml) and poured into ice-cold 5N aqueous hydrochloric acid (200 ml). The aqueous layer was separated and extracted with ethyl acetate (4×100 ml). The combined extracts were washed with 5N aqueous hydrochloric acid, water and then brine, then dried (Na₂ SO₄), filtered and the solvent removed by evaporation in vacuo, to leave a gum (6.55 g). This was chromatographed on silica gel (Merck, Kieselgel 60) with a packing ratio of 1:20 with chloroform as eluant, to afford the triazolidine-3,5-dione (4.61 g) as a gum, which later solidified. (In subsequent preparations the crude material from the reaction mixture could be triturated with hexane to induced crystallisation), m.p. 76°-8°.

The compounds shown in Table 2 were prepared in a similar manner.

                  TABLE 2                                                          ______________________________________                                          ##STR24##                                                                         Compound  R.sub.5      R.sub.4                                                                              m.p.° C.                               ______________________________________                                         5         H            C.sub.5 H.sub.11                                                                       91-2                                            6         Ph           C.sub.5 H.sub.11                                                                       109-111                                         7         Me           C.sub.5 H.sub.11                                                                       76-78                                           8         Et           C.sub.6 H.sub.13                                                                       50-52                                           9         Et           C.sub.5 H.sub.11                                                                       GUM                                             11        Me           C.sub.6 H.sub.13                                                                       75-77                                           ______________________________________                                    

EXAMPLE 5 1-(6'-Ethoxycarbonyl-n-hexyl)-4-methyl-2-(3"-oxo-n-octyl)-1,2,4-triazolidine-3,5-dione (Compound 14)

4-Methyl-2-(3'-oxo-n-octyl)-1,2,4-triazolidine-3,5-dione (4.0 g, 0.017 mol) was dissolved in hexamethylphosphoramide (60 ml) and sodium carbonate (5.0 g, 0.04 mol), sodium iodide (0.5 g) and ethyl 6-bromoheptanoate (4.327 g, 0.018 mol) in hexamethylphosphoramide (20 ml) were added and the mixture stirred at room temperature for one week. The resultant mixture was poured into water (300 ml), extracted with ethyl acetate (5×100 ml), and the combined extracts washed with water (3×200 ml), brine (2×200 ml), then dried, (Na₂ SO₄) and filtered. The ethyl acetate was removed in vacuo to leave a gum (6.77 g) which was chromatographed on silica gel (Merck, Kieselgel 60), packing ratio 1:20, using chloroform as eluant to afford 1-(6'-ethoxycarbonyl-n-hexyl)-4-methyl-2-(3"-oxo-n-octyl)-1,2,4-triazolidine-3,5-dione (3.56 g) as a gum.

I.r. (cm⁻¹): ##STR25## 5.82 q, 2H, --CO₂ CH₂ CH₃ ; 6.15 t, NCH₂ ; 6.42 t, NCH₂ ; 6.90 s, N--CH₃ ; ##STR26## --CH₂ CO₂ Et.

The compounds listed in Table 3 were prepared in a similar manner.

                  TABLE 3                                                          ______________________________________                                          ##STR27##                                                                          Compound  R.sub.5      R.sub.1                                                                             R.sub.4                                       ______________________________________                                         12         H            Et     C.sub.5 H.sub.11                                13         Ph           Et     C.sub.5 H.sub.11                                14         Me           Et     C.sub.5 H.sub.11                                15         Et           Et     C.sub.5 H.sub.11                                18         Me           Et     C.sub.5 H.sub.13                                ______________________________________                                    

Compound 12

R₅ =H, R₁ =Et, R₄ =C₅ H₁₁.

I.r. (cm⁻¹): ##STR28## --CO₂ Et.

NMR (γ): 5.95 q, 2H, CO₂ CH₂ CH₃ ; 6.15-6.8 brm, 4H, (2×N--CH₂);

(CDCl₃) 7.1-8.0 brm, ##STR29## --CH₂ CO₂ Et.

Compound 13

R₅ =Ph, R₁ =Et, R₄ =C₅ H₁₁

I.r. (cm⁻¹): ##STR30## CO₂ E.t. ##STR31## 2.2-2.9 m, 5H, C₆ H₅ ; 5.92q, 6.1-6.7 m, CO₂ CH₂ CH₃ ; (--N--CH₂ --)₂ ; ##STR32## CH₂ CO₂ Et.

Compound 18

R₅ =Me, R₁ =Et, R₄ =C₆ H₁₃

I.r. (cm): 1775, ##STR33## CO₂ Et, ##STR34## 5.95 q, CO₂ CH₂ CH₃, 2H; 6.2-6.8 m, (2×NCH₂), 4H; 7.07s, 3H, N--CH₃ ; 8.3-8.0 m, 6H, --CH₂ CO₂ C₂ H₅, ##STR35## 8.1-9.3 brm, 22H.

Analysis: Found: C, 61.50; H, 9.08; N, 10.27% C₂₁ H₃₇ N₃ O₅ requires, C, 61.29; H, 9.06; N, 10.21%.

Mass Spec: Meas, mass 411.2721, Calc. mass 411.2708.

Compound 15

R₅ =Et, R₁ =Et, R₄ =C₅ H₁₁.

I.r. (cm⁻¹): 1770, ##STR36##

N.m.r. (60 MHz, CDCl₃)τ: 5.90q, 2H, --CO₂ CH₂ CH₃ ; 6.45 quintet, 6H, (N-CH₂)₃ ; 7.1-7.9 m, 6H, ##STR37## CH₂ CO₂ Et, 8.0-9.3 brm, 23H.

EXAMPLE 6 1-(6'-Ethoxycarbonyl-n-hexyl)-2-(3"-hydroxy-n-octyl)-4-methyl-1,2,4-triazolidine-3,5-dione (Compound 21)

1-(6'-ethoxycarbonyl-n-hexyl)-2-(3"-oxo-n-octyl)-4-methyl-1,2,4-triazolidine-3,5-dione (3.56 g, 9 m mol) was dissolved in dry ethanol (60 ml) and sodium borohydride (0.375 g, 10 m mol) was added portionwise. After stirring at room temperature for 18 hr the ethanol was removed in vacuo, the residue dissolved in water (100 ml) and acidified with 5N aqueous hydrochloric acid. This aqueous mixture was extracted with ethyl acetate (4×100 ml) and the combined extracts washed with brine (2×100 ml), then dried (Na₂ SO₄), filtered and the solvent removed in vacuo, to leave a gum (3.26 g). This gum was chromatographed on silica gel (Merck, Kieselgel 60) with a packing ratio of 1:30 using benzene and benzene:ethyl acetate mixtures as eluant, to afford 1-(6'-ethoxycarbonyl-n-hexyl)-2-(3"-hydroxy-n-octyl)-4-methyl-1,2,4-triazolidine-3,5-dione (0.94 g) as a gum.

Mass Spec: Meas. mass 399.2733, calc. mass 399.2733.

I.r. (cm⁻¹): 3500, --OH; ##STR38## CO₂ Et. ##STR39## 5.18q, CO₂ CH₂ CH₃, 2H; 6.0-6.1 brm, 5H, (2×N-CH₂), CH--OH; 6.88s, 3H, --N--CH₃ ; 7.30 brs, 1H, --OH; 7.65 brt, --CH₂ CO₂ Et.

The compounds listed in Table 4 were prepared in a similar manner.

                  TABLE 4                                                          ______________________________________                                          ##STR40##                                                                       Compound         R.sub.5   R.sub.1                                                                               R.sub.4                                    ______________________________________                                         19             H         Et       C.sub.5 H.sub.11                             20             Ph        Et       C.sub.5 H.sub.11                             21             Me        Et       C.sub.5 H.sub.11                             22             Et        Et       C.sub.5 H.sub.11                             ______________________________________                                    

Compound 19

Analysis: C₁₉ H₃₅ N₃ O₅ requires C, 59.20; H, 9.15; N, 10.90%; found: C, 59.50; H, 9.39; N, 10.63%.

I.r. (cm⁻¹): 3500, --OH; ##STR41## CO₂ Et.

NMR (CCl₄)τ: 5.86 q, --CO₂ CH₂ CH₃ ; 6.1-6.7 brm, 2×N--CH₂, CH--OH, CH--OH; 7.71 brt, CH₂ CO₂ Et; 8.0-9.3 brm.

Compound 20

Analysis: C₂₅ H₃₉ N₃ O₅ requires C, 65.05; N, 9.10; H, 8.52%; Found: C, 65.13; N, 9.21; H, 8.71%.

I.r. (cm⁻¹): 3500, --OH; ##STR42## CO₂ Et

NMR (CCl₄)τ: 2.6 brm, C₆ H₅ ; 5.90 q, --CO₂ CH₂ CH₃ ; 6.1-6.9 brm, (N--CH₂), CH--OH, CH--OH; 7.75 brt, CH₂ CO₂ Et, 8.0-9.3 brm.

Compound 22

R₅ =Et, R₁ =Et, R₄ =C₅ H₁₁.

Analysis: C₂₁ H₃₉ N₃ O₅ requires C, 60.99; H 9.51; N, 10.16%; Found: C, 61.18; H, 9.47; N, 10.16%.

I.r. (cm⁻¹): 3500, --OH, ##STR43## CO₂ Et.

NMR (60 MHz, CDCl₃)τ: 5.91 brq, 3H, CH--OH, CO₂ CH₂ CH₃ ; 6.10-6.80 brm, 7H, (NCH₂)₃, CH--OH; 7.74 brt, 2H, CH₂ CO₂ Et; 8.0-9.3 brm.

Mass Spec. Meas. mass 413.2914, calc. mass 413.2889.

EXAMPLE 7 2-(3'-Hydroxy-n-octyl)-4-methyl-1,2,4-triazolidine-3,5-dione (Compound 23)

2-(3'-Oxo-n-octyl)-4-methyl-1,2,4-triazolidine-3,5-dione (0.5 g, 21 m mol) was dissolved in dry methanol (20 ml) and sodium borohydride (0.087 g, 2.3 m mol) was added portionwise. The reaction mixture was stirred overnight at room temperature and then the ethanol was removed by evaporation in vacuo. The residual gum was dissolved in water (20 ml) and acidified with 5N aqueous hydrochloric acid, then extracted with ether (4×50 ml). The combined extracts were washed with brine (3×50 ml), dried (Na₂ SO₄) and the ether removed by evaporation in vacuo to give a white residual solid, (0.36 g), m.p. 85°-88°, of 2-(3'-hydroxy-n-octyl)-4-methyl-1,2,4-triazolidine-3,5-dione (23).

Found, C, 54.77; H, 8.55%; C₁₁ H₂₁ N₃ O₃ requires, C, 54.30; H, 8.7%. I.R. (nujol, cm⁻¹): 3500, --OH; ##STR44##

NMR (60 MHz, CDCl₃)τ: 6.22 brq, 3H, N--CH₂, CH--OH; 6.90 s, 3H, --N--CH₃ ; 8.0-8.8 brm, 11H, (CH₂)₅, OH; 9.08 brt, 3H, CH₃.

EXAMPLE 8 1-(6'-Carboxy-n-hexyl)-2-(3"-hydroxy-n-octyl)-4-methyl-1,2,4-triazolidine-3,5-dione (Compound 24)

To a solution of 1-(6'-ethoxycarbonyl-n-hexyl)-2-(3"-hydroxy-n-octyl)-4-methyl-1,2,4-triazolidine-3,5-dione (0.43 g, 1.1 m mol) in dry ethanol (20 ml) was added anhydrous potassium carbonate (1.0 g) and the mixture boiled under reflux for 24 hours. The mixture was cooled, carefully acidified with ice-cold 5N aqueous hydrochloric acid and extracted with ethyl acetate (4×100 ml). The combined extracts were washed with brine, dried (Na₂ SO₄), filtered and ethyl acetate removed in vacuo to leave a gum (0.409 g). This gum was chromatographed on silica gel (Merck, Kieselgel 60) (20 g) using chloroform and chloroform-methanol mixtures (5% gradient) as eluant, to afford 1-(6'-carboxy-n-hexyl)-2-(3"-hydroxy-n-octyl)-4-methyl-1,2,4-triazolidine-3,5-dione (24) as a gum (200 mg).

Mass Spec. Meas. mass 371.2416, calc. mass 371.2421.

I.r. (cm⁻¹): 2400-3600, CO₂ H, OH; 1640-1800, CO₂ H, ##STR45## 3.32 brs, 2H, CO₂ H OH; 6.4 brm, 5H, CH--OH, (N--CH₂)₂ ; 6.97s, 3H, N--CH₃ ; 7.70 brt, 2H, CH₂ CO₂ H.

EXAMPLE 9 1-(6'-Ethoxycarbonyl-n-hexyl)-2-(3"-hydroxy-3"-methyl-n-nonyl)-4-methyl-1,2,4-triazolidine-3,5-dione (Compound 25)

To a solution of 1-(6"-ethoxycarbonyl-n-hexyl)-(3"-oxo-n-nonyl)-4-methyl-1,2,4-triazolidine-3,5-dione (18) (0.82 g, 0.002 mol) in tetrahydrofuran (20 ml) cooled to -78° under a nitrogen atmosphere, methyl lithium (1.1. ml, 2.2 m mol) as a 2M solution in ether was added dropwise. After complete addition the reaction mixture was stirred for a further 1 hr at -78°, allowed to warm to ca. -20° and then quenched with saturated ammonium chloride solution (20 ml). This mixture was extracted with ethyl acetate (4×50 ml); the combined extracts washed with brine (2×50 ml) dried (Na₂ SO₄) and the solvent removed in vacuo to leave a gum (812 mg). This gum was chromatographed on silica gel (Merck, Kieselgel 60, 20 g) using chloroform as eluant to afford 1-(6'-ethoxycarbonyl-n-hexyl)-2-(3"-hydroxy-3"-methyl-n-nonyl)-4-methyl-1,2,4-triazolidine-3,5-dione (25) as a yellow gum (252 mg).

Mass spec. C₂₂ H₄₁ N₃ O₅ requires M⁺ 427; found: M⁺ 427 (100%) Major 412 (M-Me, ca. 10%); 382 (M-OEt,ca30%) 342 (M-C₆ H₁₃,ca.50%), 324(M-H₂ O,C₆ H₁₃, ca. 20%); 322 (M-CH₄, C₆ H₁₃, 20%), 296 (M-H₂ O, C₂ H₄, C₆ H₁₃, 30%); 284 (M-C₉ H₁₉ O, 80%); 226 (M-C₁₂ H₂₅ O₂, 100%) 128 (M-C₁₈ H₃₅ O₃, 80%).

I.r. (cm⁻¹): 3500, --OH; ##STR46## CO₂ Et. ##STR47## 5.84q, 2H, CO₂ CH₂ CH₃ ; 4.05-4.55m, 4H, (N--CH₂)₂ ; 6.92s, 3H, N--CH₃ ; 7.32brs, 1H, --OH, 7.70 brt, 2H,CH₂ CO₂ Et.

The following Examples illustrate the preparation of the active compounds of the invention by the (XIII)→(XVII)→(XV)→(I) route, as illustrated in the flow diagram.

EXAMPLE 10 Preparation of hept-6-enoic acid ##STR48##

Ref: E. A. Brande, R. P. Linstead, and K. R. H. Wooldridge, JCS, 1956, 3074.

To a solution of sodium (19 g, 0.826 g atom) in ethanol (250 ml) at room temperature was added, dropwise, with stirring diethyl malonate (158 g, 1.0 mol) in ethanol (100 ml) and the mixture stirred for a further 1 hr at room temperature after complete addition.

To this mixture was added dropwise with stirring 5-bromopent-1-ene (100 g, 0.671 mol) in ethanol (50 ml) and after addition was complete the mixture was stirred for a further 12 hr at room temperature. This resultant mixture was acidified by the addition of acetic acid (15 ml) and the ethanol was removed in vacuo. The residue was mixed with ether (500 ml), filtered and the filtrate was washed with saturated sodium chloride solution until neutral. The organic phase was then dried (Na₂ SO₄) filtered and the ether removed in vacuo. The resultant liquid was distilled to afford diethyl-pent-4-enylamalonate b.p. 131°-6°/ 14 mm (80 g) (ref. b.p. 134°/14 mm).

The diethyl-pent-4-enylmalonate (80 g, 0.351 mol) was added to a solution of potassium hydroxide (120 g, 2.143 mol) in water (75 ml) containing ethanol (15 ml) and the resultant mixture stirred for 12 hr at room temperature. This mixture was then acidified with 5N sulphuric acid (ca.250 ml) and concentrated sulphuric acid (ca.25 ml) and the resultant mixture extracted with ether (3×200 ml). The combined extracts were washed with water (2×200 ml) and saturated sodium chloride solution (2×200 ml). The organic phase was dried (Na₂ SO₄), filtered and the ether removed from the filtrate in vacuo. The residual oil was decarboxylated at a bath temperature of 160° and pressure 20 mm Hg and the hept-6-enoic acid collected at 120°/20 mm. (38.2 g) (ref. b.p. 74°/0.5 mm).

EXAMPLE 11 (a) Preparation of 1-(6'-methoxycarbonyl-n-hexyl)-4-methyl-1,2,4-triazolidine-3,5-dione (26) ##STR49##

Dinitrogen tetroxide was bubbled through a suspension of 4-methyl-1,2,4-triazolidine-3,5-dione (23.0 g, 0.2 mol) in dichloromethane (250 ml) cooled to 0° C., until a clear, homogenous deep red solution was obtained. This solution was then dried (Na₂ SO₄), filtered, and the filtrate evaporated at room temperature in vacuo to give 4-methyl-1,2,4-triazolidine-3,5-dione (m.p. 105° decomp). To the 4-methyl-1,2,4-triazolidine-3,5-dione (23.0 g, 0.2 mol) dissolved in benzene (200 ml) was added dropwise hept-6-enoic acid (23.0 g, 0.18 mol) in benzene (100 ml) and the resultant solution boiled under reflux in an atmosphere of nitrogen, until a pale yellow solution has been obtained (in 1 hr). The resultant solution was evaporated in vacuo and the residue dissolved in a 10% solution of acetyl chloride in methanol (300 ml). This solution was boiled at reflux for 5 hr, stirred at room temperature overnight and then evaporated in vacuo. The residue (44 g) was chromatographed on silica gel (Merck Kieselgel 60, 900 g) using chloroform; methanol as eluant (0-5% methanol), to afford 1-(6'-methoxycarbonyl-n-hex-2-enyl)-4-methyl-1,2,4-triazolidine-3,5,-dione (19.1 g) m.p. 55-7.

Found: C, 51.55; H, 6.56; N 16.59%; C₁₁ H₁₇ N₃ O₄ requires C, 51.76; H, 6.71; N 16.46%.

NMR (CDCl₃)τ: 0.8-1.2 brs, 1H, N--H; 4.37m, 2H, CH═CH; 5.97 brd, 2H, N--CH₂ --; 6.40 s. 3H, --CO₂ CH₃ ; 7.00, S, 3H, N--CH₃ ; 7.5-8.8 brm, 6H, --(CH₂ --₃.

IR (cm⁻¹): ##STR50## CO₂ Me;

Mass Spec. Meas. mass 255.1243 calc. mass 255.1219.

(b) Preparation of 1-(6'-methoxycarbonyl-n-hexyl)-4-methyl-1,2,4-triazolidine-3,5-dione

The 1-(6'-methoxycarbonyl-n-hex-2-enyl)-4-methyl-1,2,4-triazolidine-3,5-dione (12.4 g, 0.0486 mol) was dissolved in dimethoxyethane (200 ml) and 10% palladium on charcoal (3 g) was added and the resultant mixture was allowed to take up hydrogen (ca. 1100 mls). After the reaction was complete the resultant mixture was filtered through a kieselguhr bed and the filtrate evaporated in vacuo to afford 1-(6'-methoxycarbonyl-n-hexyl)-4-methyl-1,2,4-triazolidine-3,5-dione (12.3 g).

m.p. 80°-1°.

Found: C, 51.12; H, 7.71; N 16.38%; C₁₁ H₁₉ N₃ O₄ requires C, 51.35; H, 7.44; N, 16.33%.

NMR (CDCl₃)τ: 6.39 s, 6.48 m, 5H, --CO₂ CH₃ ; --N--CH₂ --; 6.97s, 3H, N--CH₃ ; 7.73 m, 2H, --CH₂ CO₂ Me; 9.07-9.78 brm, --(CH₂)₄, 8H.

IR (nujol) cm⁻¹ : ##STR51## CO₂ Me.

Mass Spec: Meas. mass 257.1377 calc. mass 257.1375.

EXAMPLE 12 Preparation of 1-(p-toluenesulphonyl)-3-cyclohexylbutan-3-ol

To a slurry of zinc (33 g, 0.5 mol) in benzene (50 ml) containing a small crystal of iodine, boiled at reflux, was added carefully 40 ml of a mixture of cyclohexylmethyl ketone (37 g, 0.294 mol), ethyl bromoacetate (84 g, 0.5 mol) and benzene (50 ml). After initiation of the reaction, the rest of the mixture was added at such a rate that reflux was maintained. After complete addition of the ketone mixture the resultant reaction mixture was boiled at reflux for a further 1 hr. The mixture was then cooled and poured into ice-cold 20% sulphuric acid (200 ml) and extracted with ether (4×200 ml). The combined extracts were washed with water (2×250 ml), saturated sodium hydrogen carbonate solution (2×250 ml) and saturated sodium chloride solution until neutral. The extract was then dried (Na₂ SO₄), filtered and the filtrate evaporated in vacuo to remove ether to give an oil (97 g). This residual oil was then distilled to afford ethyl-3-cyclohexyl-3-hydroxy-butyrate, (36 g) b.p. 90°-94°/0.05 mm.

To a slurry of lithium aluminium hydride (6.39 g, 0.168 mol) in ether (250 ml), in an atmosphere of nitrogen and cooled in an ice-bath was added dropwise ethyl-3-cyclohexyl-3-hydroxy-butyrate (36 g, 0.168 mol) in ether (100 ml). After complete addition of the ester the resultant mixture was boiled at reflux for 1 hr, then cooled in an ice-bath. Excess lithium aluminium hydride was destroyed by successive dropwise addition of water (7 ml), 10% sodium hydroxide solution (7 ml) and water (21 ml). The reaction mixture was filtered, the filter cake washed with ether (2×100 ml) and the filtrate washed with saturated sodium chloride solution (1×250 ml) and then dried (Na₂ SO₄). This mixture was filtered and the filtrate evaporated in vacuo to remove ether to give 3-cyclohexylbutane-1,3-diol (25 g) as an oil.

NMR (CDCl₃)₂ τ: 5.51, 1H, --OH; 6.26 brm, 3H, --OH, CH₂ --OH; 8.0-9.5 brm, 8.92 s, 16H, --(CH₂ --₆, --CH--, CH₃.

IR (cm⁻¹) 3500, --OH.

The 3-cyclohexylbutan-1,3-diol (25 g, 0.145 mol) was dissolved in pyridine (130 ml) and cooled to 0° C. with stirring. Toluene sulphonyl chloride (29 g, 0.152 mol) was added portionwise and the resultant reaction mixture stirred for 45 minutes at 0°. The reaction mixture was then stored in a refrigerator for 15 hr and then poured into iced-water (200 ml). The reaction mixture was extracted with ether (3×200 ml) and the combined extracts washed with 10% HCL (2×200 ml), saturated sodium chloride solution (3×200 ml) and then dried (Na₂ SO₄). This mixture was filtered and the filtrate evaporated in vacuo at room temperature to remove ether to leave a gum (45 g). This gum was mixed with petrol (bp 60°-80°, 200 ml) gradually cooled to -78° with stirring, and the petrol decanted. Residual petrol was removed by evaporation in vacuo at room temperature to leave 1-(p-toluene sulphonyl)- 3-cyclohexybutan-3-ol (40 g) as a gum.

Found: C, 62.36; H, 7.99; S, 9.40%; C₁₇ H₂₆ SO₄ requires C, 62.56; H, 8.03; S, 9.80%.

IR (cm⁻¹): 3600, OH; ##STR52##

The ethyl hydroxyesters and corresponding tosylates given in Table 1. were prepared in a similar manner.

                                      TABLE 5                                      __________________________________________________________________________     Characterising data for ethyl-3-alkyl(aryl)-3-hydroxy alkanoates (4) and       1-(p-toluene sulphonyl)-                                                       3-alkyl(aryl) alkan-3-ols(3).                                                   ##STR53##                                                                                             ##STR54##                                                                     TOSYLATE (27)                                           ESTER (28)             ANALYSIS, found (calcd)                                                                          I.R. cm.sup.-1                        R.sub.4     R.sub.2                                                                            b.p.°/mmHg                                                                       C     H     S   OH  OTS                               __________________________________________________________________________     C.sub.6 H.sub.13                                                                           CH.sub.3                                                                           84.88/0.1                                                                             62.39(62.18)                                                                         8.89(8.59)                                                                           9.27(9.76)                                                                           3550                                                                               1180 br                            ##STR55##  CH.sub.3                                                                           92-6/0.1                                                                              63.64(63.74)                                                                         6.37(6.29)                                                                           9.78(9.99)                                                                           3580                                                                               1185,1195                          ##STR56##  CH.sub.3                                                                           102-106/0.5                                                                           64.66(64.66)                                                                         7.11(6.63)                                                                           8.94(9.57)                                                                           3600                                                                               1190 br                            ##STR57##  CH.sub.3                                                                           84-86/0.1                                                                             62.05(62.18)                                                                         9.04(8.59)                                                                           9.31(9.76)                                                                           3600                                                                               1180,1190                          ##STR58##  CH.sub.3                                                                           90-4/0.05                                                                             62.36(62.56)                                                                         7.99(8.03)                                                                           9.40(9.80)                                                                           3600                                                                               1185,1195                          ##STR59##  CH.sub.3                                                                           116/118/0.07                                                                          64.95(64.66)                                                                         6.65(6.63)                                                                             --  3550                                                                               1185,1195                          ##STR60##  CH.sub.3                                                                           50-54/0.05                                                                            61.55(59.14)                                                                         7.61(7.09)                                                                           10.95(11.25)                                                                         3550                                                                               1185,1190                           C.sub.9 H.sub.19                                                                         CH.sub.3                                                                           132/134/0.05                                                                          64.82(64.8)                                                                          9.57(9.25)                                                                           8.6(8.64)                                                                            3550                                                                               1180,1190                          ##STR61##  CH.sub.3.sup.2                                                                            67.26(67.32)                                                                         8.19(8.22).sup.1                                                                       --  3400                                                                               1180,1190                          ##STR62##  CH.sub.3.sup.3               3550                                                                               1180,1190                          ##STR63##  CH.sub.3                                                                           102-104/0.05                                                                            --    --    --  3600                                                                               1185,1195                          ##STR64##  CH.sub.3                                                                           GUM.sup.4                                                                               --    --    --  3550                                                                               1180 br                           __________________________________________________________________________      .sup.1 Diol analysed due to decomposition of tosylate                          .sup.2 not purified due to decomposition                                       .sup.3 Diol purified by chromatography                                         .sup.4 Purified by chromatography                                        

EXAMPLE 13 (a) Preparation of 1-(6'-methoxycarbonyl-n-hexyl-)-2-(3"-hydroxy-3"-methyl-n-nonyl)-4-methyl-1,2,4-triazolidine-3,5-dione (29) (by procedure 1) ##STR65##

To a solution of 1-(6'-methoxycarbonyl-n-hexyl)-4-methyl-1,2,4-triazolidine-3,5-dione(26) (6.428 g, 0.025 mol) in hexamethylphosphoramide (40 ml) was added sodium carbonate (3.18 g, 0.03 mol), sodium iodide (1 g, 0.007 mol) and 1-(p-toluenesulphonyl)-3-methylnonan-3-ol (8.204 g, 0.025 mol) in hexamethylphosphoramide (30 ml) and the resultant mixture stirred at room temperature for 70 hr. The reaction mixture was then poured into water (200 ml), acidified with 10% hydrochloric acid and extracted with ethyl acetate (3×200 ml). The combined extracts were washed with water (3×250 ml) saturated sodium chloride solution (3×250 ml) and then dried (Na₂ SO₄). This mixture was filtered and the filtrate evaporated in vacuo to remove ethyl acetate to leave a gum (9.54 g). This gum was chromatographed on silica gel (Merck Kieselgel 60) (500 g) using chloroform:methanol as eluant (0-2% methanol) to afford 1-(6'-methoxy-carbonyl-n-hexyl)-2-(3"-hydroxy-3"-methyl-n-nonyl)-4-methyl-1,2,4-triazolidine-3,5-dione(29) (2.95 g) as a gum.

found: C, 60.51; H 9.72; N, 10.05%; C₂₁ H₃₉ N₃ O₅ requires C, 60.99; H, 9.51; N 10.16%.

NMR (CDCl₃)τ: 6.35s, 6.36m, 7H, --CO₂ CH₃, (N--CH₂)₂ ; 6.96s, 3H, --N --CH₃ ; 7.46-7.84, 3H, CH₂ --CO₂ Me; --OH 8.01-8.90 m, 8.81s, 9.11 m, 26H, --CH₂)₁₀, CH₃ --C--OH, --CH₂ CH₃.

IR (cm⁻¹): 3500, --OH; 1770 ##STR66## CO₂ Me.

Mass Spec: found M⁺ 413.2829. Calc. M⁺ 413.2769.

(b) Preparation of 1-(6'-methoxycarbonyl-n-hexyl)-2-(3"-hydroxy-3"-cyclopropyl-n-butyl)-4-methyl-1,2,4-triazolidine-3,5-dione (35) (by procedure 2) ##STR67##

To a solution of 1-(6'-methoxycarbonyl-n-hexyl)-4-methyl-1,2,4-triazolidine-3,5-dione (2.0 g, 0.0078 mol) in N,N-dimethylformamide (20 ml) stirred at room temperature was added portionwise sodium hydride (0.26 g, 0.0087 mol) as an 80dispersion in mineral oil and the mixture stirred for 0.5 hr at room temperature. To this solution was added anhydrous lithium iodide (2.3 g, 0.017 mol) and the resultant mixture stirred for a further 0.5 hr at room temperature. To this resultant solution was added 1-(p-toluene sulphonyl)-3-cyclopropylbutan-3-ol (2.22 g, 0.0078 mol) in N,N-dimethylformamide (20 ml) and the reaction mixture was stirred for 24 hr at 50°. The reaction mixture was then poured into water (200 ml), acidified with 10% hydrochloric acid and extracted with ethyl acetate (3×250 ml). The combined extracts were washed with water (3×250 ml) and saturated sodium chloride solution (2×250 ml) and then dried (Na₂ SO₄), filtered and the filtrate evaporated in vacuo to remove ethyl acetate to afford a gum (3.51 g). This gum was chromatographed on silica gel (Merck Kieselgel 60, 200 g) using chloroform:methanol as eluant (methanol 0-2%) to afford 1-(6'-methoxycarbonyl-n-hexyl)-2-(3"-hydroxy-3"-cyclopropyl-n-butyl)-4-methyl-1,2,4-triazolidine-3,5-dione (35) as a gum (558 mg).

The 1,2,4-trisubstituted-1,2,4-triazolidine-3,5-diones given in Table 6 were prepared in a similar manner using either procedure (1) or (2); except (i) the acids (wherein ##STR68## which were prepared by the procedure illustrated in Example 14, and (ii) the unsaturated olefinic analogues (wherein Y is CH═CH) which were prepared by the procedure illustrated in Example 15.

The characterising data for these compounds is given in a separate section.

                                      TABLE 6                                      __________________________________________________________________________     1,2,4-trisubstituted-1,2,4-triazolidine-3,5-diones                              ##STR69##                                                                     No:                                                                               R.sub.1                                                                           R.sub.2                                                                           R.sub.3                                                                           R.sub.4                                                                               R.sub.5                                                                              Y     n Procedure                                     __________________________________________________________________________     29 CH.sub.3                                                                          CH.sub.3                                                                          OH C.sub.6 H.sub.13                                                                      CH.sub.3                                                                             CH.sub.2CH.sub.2                                                                     3 1                                             30 CH.sub.3                                                                          CH.sub.3                                                                          OH C.sub.6 H.sub.5                                                                       CH.sub.3                                                                             CH.sub.2CH.sub.2                                                                     3 1                                             31 CH.sub.3                                                                          CH.sub.3                                                                          OH C.sub.6 H.sub.5 CH.sub.2                                                              CH.sub.3                                                                             CH.sub.2CH.sub.2                                                                     3 1                                               32                                                                              CH.sub.3                                                                          CH.sub.3                                                                          OH                                                                                 ##STR70##                                                                            CH.sub.3                                                                             CH.sub.2CH.sub.2                                                                     3 1                                               33                                                                              CH.sub.3                                                                          CH.sub.3                                                                          OH                                                                                 ##STR71##                                                                            CH.sub.3                                                                             CH.sub.2CH.sub.2                                                                     3 1                                               34                                                                              CH.sub.3                                                                          CH.sub.3                                                                          OH                                                                                 ##STR72##                                                                            CH.sub.3                                                                             CH.sub.2CH.sub.3                                                                     3 1                                               35                                                                              CH.sub.3                                                                          CH.sub.3                                                                          OH                                                                                 ##STR73##                                                                            CH.sub.3                                                                             CH.sub.2CH.sub.2                                                                     3 2                                               36                                                                              CH.sub.3                                                                          CH.sub.3                                                                          OH C.sub.9 H.sub.19                                                                      CH.sub.3                                                                             CH.sub.2CH.sub.2                                                                     3 1                                               37                                                                              CH.sub.3                                                                          CH.sub.3                                                                          OH                                                                                 ##STR74##                                                                            CH.sub.3                                                                             CH.sub.2CH.sub.2                                                                     3 1                                               38                                                                              CH.sub.3                                                                          CH.sub.3                                                                          OH                                                                                 ##STR75##                                                                            CH.sub.3                                                                             CHCH  3 1                                               39                                                                              CH.sub.3                                                                          CH.sub.3                                                                          OH                                                                                 ##STR76##                                                                            CH.sub.3                                                                             CH.sub.2CH.sub.2                                                                     3 1                                               40                                                                              CH.sub.3                                                                          CH.sub.3                                                                          OH CH.sub.3                                                                              CH.sub.3                                                                             CH.sub.2CH.sub.2                                                                     3 1                                             41 H  CH.sub.3                                                                          OH C.sub.6 H.sub.13                                                                      CH.sub.3                                                                             CH.sub.2CH.sub.2                                                                     3 --                                            42 H  CH.sub.3                                                                          OH C.sub.6 H.sub.5                                                                       CH.sub.3                                                                             CH.sub.2CH.sub.2                                                                     3 --                                            43 CH.sub.3                                                                          CH.sub.3                                                                          OH C.sub. 6 H.sub.13                                                                     CH.sub.3                                                                             CHCH  3 1                                             44 H  CH.sub.3                                                                          OH C.sub.6 H.sub.13                                                                      CH.sub.3                                                                             CHCH  3 --                                              45                                                                              CH.sub.3                                                                          CH.sub.3                                                                          OH C.sub.6 H.sub.13                                                                       ##STR77##                                                                           CH.sub.2CH.sub.2                                                                     3 1                                               46                                                                              CH.sub.3                                                                          CH.sub.3                                                                          OH C.sub.6 H.sub.13                                                                      Ph    CH.sub.2CH.sub.2                                                                     3 1                                               47                                                                              CH.sub.3                                                                          CH.sub.3                                                                          OH C.sub.6 H.sub.13                                                                       ##STR78##                                                                           CH.sub.2CH.sub.2                                                                     3 1                                               48                                                                              H  CH.sub.3                                                                          OH C.sub.6 H.sub.13                                                                       ##STR79##                                                                           CH.sub.2CH.sub.2                                                                     3 --                                              49                                                                              CH.sub.3                                                                          CH.sub.3                                                                          OH C.sub.6 H.sub.13                                                                      PhCH.sub.2                                                                           CHCH  3 1                                             __________________________________________________________________________

EXAMPLE 14 Preparation of 1-(6'-carboxy-n-hexyl)-2-(3"-hydroxy-3"-methyl-n-nonyl)-4-methyl-1,2,4-triazolidine 3,5-dione (41) ##STR80##

To a solution of 1-(6'-methoxycarbonyl-n-hexyl)-2(3"-hydroxy-3"-methyl-n-nonyl)-4-methyl-1,2,4-triazolidine-3,5-dione (5) (2.423 g, 0.006 mol) in methanol (100 ml) was added a 10% aqueous solution of sodium carbonate (30 ml) and the mixture boiled at reflux for 18 hr. The reaction mixture was cooled and evaporated in vacuo. The residue was dissolved in water (100 ml) and extracted with ether (3×100 ml). The aqueous phase was then acidified with 10% hydrochloric acid and reextracted with ethyl acetate (3×200 ml). The combined extracts were washed with saturated sodium chloride solution (2×200 ml) dried (Na₂ SO₄), filtered and the filtrate evaporated in vacuo to remove ethyl acetate to afford 1-(6'-carboxy-n-hexyl)-2-(3"-hydroxy-3"-methyl-n-nonyl)-4-methyl-1,2,4-triazolidine-3,5-dione (41) as a gum (2.404 g).

EXAMPLE 15

Preparation of 1-(6'-methoxycarbonyl-n-hex-2-enyl)-2-(3"-hydroxy-3"-methyl-n-nonyl)-4-methyl-1,2,4-triazolidine-3,5-dione (43) was carried out as in Procedure (1) of Example 13 using 1-(6'-methoxycarbonyl-n-hex-2-enyl)-4-methyl-1,2,4-triazolidine-3,5-dione instead of 1-(6'-methoxycarbonyl-n-hexyl)-4-methyl-1,2,4-triazolidine-3,5-dione.

CHARACTERISING DATA FOR COMPOUNDS GIVEN IN TABLE 2 Compound 30

NMR (CDCl₃)τ: 2.45-2.82 brm, 5H, --C₆ H₅ ; 6.295, 6.30-6.77 brm, 7H, --CO₂ CH₃, --N--CH₂)₂ ; 7.015, N--CH₃, 3H 7.25s, 1H, --OH (exchanged with D₂ O); 7.51-8.09 m, 8.41 s, 8.69 brs, 15H.

IR (cm⁻¹): 3500, --OH; ##STR81##

Mass Spec. found M⁺ 405.2258 Calc. C₂₁ H₃₁ N₃ O₅ : 405.2252

Compound 31

Analysis: found: C, 62.51; H, 8.23; N, 9.96%; C₂₂ H₃₃ N₃ O₅ requires C, 62.99; H, 7.93; N, 10.02%.

NMR(CDCl₃)τ: 2.75 s, 5H, --C₆ H₅ ; 6.32m, 6.36s, 7H, (N--CH₂)₂, CO₂ CH₃ ; 6.96s, 3H, --N--CH₃ ; 7.23s, 2H, C₆ H₅ CH₂ --; 7.54s, 7.70t, 3H, --OH, CH₂ CO₂ Me; 8.09-9.08m, 8.81s, --(CH₂)₅, CH₃ C--OH, 13H.

IR (cm⁻¹): 3500, --OH; ##STR82## CO₂ CH₃.

Mass Spec: found M⁺ 419.2429 Calc. C₂₂ H₃₃ N₃ O₅ : 419.2420.

Compound 32

NMR (CDCl₃)τ: 6.32m, 6.34 s, 7H, (n--CH₂)₂, CO₂ CH₃ ; 6.95s, N--CH₃, 3H; 7.75m, 3H, --OH, CH₂ CO₂ Me; 8.1-9.4m, 8.88s, 26H, --(CH₂)₈ ; CH--CH₃ ; CH₃ --C--OH, CH₃ --CH₂.

IR (cm⁻¹): 3500, --OH; ##STR83##

Mass Spec. found M⁺ Calc. C₂₁ H₃₉ N₃ O₅ ; 413.2959, 413.2889.

Compound 33

NMR (CDCl₃)τ: 6.31s, 6.37m, 7H, CO₂ Me, --(N--CH₂)₂ ; 6.93s, 3H, N--CH₃ ; 7.67m, 3H, --OH, CH₂ CO₂ Me 7.98-9.30m, 8.86s, 24H, --(CH₂)₁₀, CH--CH₂, CH₃ --C--OH.

IR (cm⁻¹): 3500, --OH; ##STR84## CO₂ Me

Mass Spec. found M⁺ 411.2690 Calc.: M⁺ C₂₁ H₃₇ N₃ O₅ 411.2647.

Compound 34

Analysis: found; C 63.34; H, 7.71; N 10.08%; C₂₂ H₃₃ N₃ O₅ requires C, 62.99; H, 7.93; N, 10.02%.

NMR (CDCl₃)τ: 2.60-2.93m, 4H, C₆ H₄ ; 6.33 s, 3H, --CO₂ CH₃ ; 6.58 brt, 4H, (--NCH₂)₂ ; 7.04s, 3H, --N--CH₃ ; 7.66s, 7.50-8.68 brm, 8.45s, 19H, C₆ H₅ --CH₃, --OH; (--CH₂ --)₆, CH₃ --.

IR (cm⁻¹): 3550, --OH; ##STR85##

Mass Spec. found M⁺ 419.2446 Calcd. M⁺ C₂₂ H₃₃ N₃ O₅, 419.2420.

Compound 35

NMR (CDCl₃)τ: 6.00-6.77 brm, 6.35s, 7H, (N--CH₂)₂, --CO₂ CH₃ ; 6.96s, 3H, N--CH₃ ; 7.69 brt, 3H, --OH, CH₂ CO₂ Me; 8.0-9.37 brm, 8.82s, 14H, (CH₂)₅, CH₃, CH<; 9.4-9.8 brm, 4H, (CH₂)₂.

IR (cm⁻¹): 3500, --OH; ##STR86##

Mass Spec: found Mass 369.2246 Calc. mass 369.2247.

Compound 36

Analysis: Found: C, 62.90; H, 9.74; N, 9.26%. C₂₄ H₄₅ N₃ O₅ requires: C, 63.27; H, 9.95; N, 9.22%.

NMR (60 MHz, CDCl₃)τ: 6.0-6.45 m, 6.35 s, (N--CH₂)₂, --CO₂ CH₃ ; 6.95 s, 3H, N--CH₃ ; 7.5-7.85 m, 3H, CH₂ CO₂ CH₃, OH; 8.0-8.8 brm, 29H, 9.1 brt, 3H, --CH₃.

I.r. (cm⁻¹): 3550, --OH; ##STR87##

Compound 37

Analysis: Found: C60.49; H, 7.92; N, 9.52%. C₂₂ H₃₃ N₃ O₆ requires: C, 60.67; H, 7.64; N, 9.65%.

NMR (60 MHz, CDCl₃)τ: 2.6-3.25 m, 4H, --C₆ H₄ ; 6.2 s, 3H, --OCH₃ ; 6.35 s, 3H, CO₂ CH₃ ; 6.4-6.8 m, 4H, (N--CH₂)₂ ; 7.05 s, 3H, N--CH₃ ; 7.45 brs, 1H, --OH; 7.6-8.2 brm, CH₂ --C(OH), CH₂ CO₂ Me; 8.2-8.9 brm, 8.46 s, 11H, (CH₂)₄, CH₃ --C--OH.

I.r. (cm⁻¹): 3500, --OH; ##STR88##

Compound 38

NMR (60 MHz, CDCl₃)τ: 2.0-2.62 m, 7H, --C₁₀ H₇ ; 4.62 brq, 2H, --CH═CH; 5.93-6.13 brm, 2H, --CH₂ --CH═CH; 6.34 s, 6.23-6.60 brm, 6H, CO₂ CH₃, N--CH₂, --OH; 7.18 s, 3H, --NCH₃ ; 7.62-8.50 brm, 8.34 s, 11H.

I.r. (cm⁻¹): 3500, --OH, ##STR89##

Compound 39

NMR (CDCl₃, 60 MHz)τ: 2.47-3.15 m, 4H, C₆ H₄ ; 6.36 s, 6.36-6.74 brm, 6.90 brs, 7.04 s, 11H, --CO₂ CH₃, --(NCH₂)₂, --OH, --N--CH₃ ; 7.55-8.15 brm, 8.30-8.90 brm, 8.50 s, 15H, (CH₂)₆, --CH₃.

I.r. (cm⁻¹): 3500, --OH; ##STR90## 1602, aromatic.

Mass Spec. Meas. mass, 423.2198; calc. mass, M⁺, 423.2170.

Compound 40

NMR 9CDCl₃, 60 MHz)τ: 6.12-6.58 brm, 6.30 s, 7H, (N--CH₂)₂, --CO₂ CH₃ ; 6.91 s, 3H, --N--CH₃ ; 7.50-8.90 brm, 8.70 s, 19H.

I.r. (cm⁻¹): 3500, --OH; ##STR91## CO₂ Me.

Mass Spec. Meas. mass, 343.2097; calc. mass, M⁺, 343.2107.

Compound 41

Analysis: Found: C, 59.61; H, 9.57; N, 10.38%. C₂₀ H₃₇ O₅ N₃ requires: C, 60.13; H, 9.33; N, 10.52%.

NMR (60 MHz, DMSO)τ: 6.2-6.7 brm, 4H, (N--CH₂)₂ ; 7.09 s, 3H, N--CH₃ ; 7.81 brt, 2H, CH₂ CO₂ H; 8.2-9.4 brm, 9.93 s, 9.12 brt, 26H, --CH₂ --₁₀, CH₃, CH₂ CH₃.

I.r. (cm⁻¹): 2500-3500, OH; ##STR92##

Mass Spec. Meas. mass 399.2688; calc. mass 399.2734.

Compound 42

Analysis: Found: C, 60.93; H, 7.62; N, 10.72%. C₂₀ H₂₉ N₃ O₅ requires: C, 61.36; H, 7.47; N, 10.73%.

NMR (60 MHz, CDCl₃)τ: 2.5-2.85 brm, 5H, --C₆ H₅ ; 3.72 brs, 2H, CO₂ H, OH; 6.15-6.85 brm, 4H, (N--CH₂)₂ ; 7.05 s, 3H, N--CH₃ ; 7.50-8.15 brm, 8.44 s, 8.72 brs, 15H.

I.r. (cm⁻¹): 2500-3500, --OH; ##STR93##

Mass Spec. Meas. mass M⁺ 391.2116; calc. mass 391.2107.

Compound 43

NMR (60 MHz, CDCl₃)τ: 3.92-4.92 m, 2H, CH═CH; 5.84 d, 2H, J=5 Hz, CH₂ --CH═CH--; 6.26 m, 6.30 s, 5H, --N--CH₂, --CO₂ CH₃ ; 6.91 s, 3H, N--CH₃ ; 7.55-8.82 m, 8.76 s, 9.06 m, 25H.

I.r. (cm⁻¹): 3600, OH; ##STR94## CO₂ Me.

Mass Spec. Meas. mass (for M⁺ --C₆ H₁₃), 326.1700; Calc. mass, 326.1716. No M⁺.

Compouhd 44

NMR (CDCl₃, 60 MHz)τ: 4.20-4.60 brm, 2H, CH═CH; 4.90 brs, 2H, --CO₂ H, --OH; 5.85 brd, 2H, N--CH₂ ; 6.10-6.45 m, 2H, N--CH₂ ; 6.91 s, 3H, N--CH₃ ; 7.50-9.20 brm, 8.77 s, 9.08 brt.

I.r. (cm⁻¹): 2600-3500, --OH; ##STR95##

Mass Spec. Meas. mass, 397.2573; calc. mass, 397.2577.

Compound 45

NMR (CDCl₃, 60 MHz)τ: 5.5-5.7 brt, 1H, CH--N; 6.1-6.65 brt, 4H, (--NCH₂)₂ ; 6.35 s, 3H, CO₂ CH₃ ; 7.55-7.85 m, 3H, CH₂ CO₂ CH₃, OH; 7.85-9.0 m, 33H, --(CH₂)₄, C₅ H₁₀ --CH--N, (CH₂)₆, CH₃ ; 9.1 m, 3H, CH₂ CH₃.

I.r. (cm⁻¹): 3500, OH; ##STR96## CO₂ CH₃.

Mass spec. Meas. mass, M⁺, 481.3539; calc. mass, M⁺, 481.3516.

Compound 46

NMR (CDCl₃, 60 MHz)τ: 2.55-2.65 m, 5H, C₆ H₅ ; 6.05-6.5 brt, 4H, (--NCH₂)₂ ; 6.33 s, 3H, CO₂ CH₃ ; 7.55-7.85 m, 3H, CH₂ CO₂ CH₃, OH; 7.85-9.0 m, 23H, --(CHH₂)₄ --, ##STR97## 9.1 m, 3H, CH₂ CH₃.

I.r. (cm⁻¹): 3500, OH; ##STR98## CO₂ CH₃.

Mass spec. Meas. mass, M⁺, 475.3027; calc. mass, M⁺, 475.3008.

Compound 47

Analysis: Found: C, 65.96; H, 8.56; N, 8.26%. C₂₇ H₄₃ N₃ O₅ requires: C, 66.23; H, 8.85; N, 8.58%.

NMR (CDCl₃, 60 MHz)τ: 2.6-2.9 m, 4H, C₆ H₄ ; 6.0-6.45 brt, 4H, --(NCH₂)₂ ; 6.35 s, 3H, CO₂ CH₃ ; 7.5-7.8 m, 3H, CH₂ CO₂ CH₃, OH; 7.6 s, 3H, C₆ H₄ CH₃ ; 7.8-9.0 m, 23H, --(CH₂)₄ --, ##STR99## 9.1 m, 3H, CH₂ CH₃.

I.r. (cm⁻¹): 3500, OH; ##STR100## CO₂ CH₃ ;

Mass Spec. Meas. mass, M⁺, 489.3237; calc. mass, M⁺, 489.3203.

Compound 48

NMR (CDCl₃, 60 MHz)τ: 2.6-2.9 m, 4H, C₆ H₄ ; 4.1 s, 1H, CO₂ H; 6.05-6.4 brt, 4H, --(NCH₂)₂ ; 7.65 s, 3H, C₆ H₄ CH₃ ; 7.65-7.8, 3H, CH₂ CO₂ CH₃, OH; 7.8-9.0 m, 23H, --(CH₂)₄, ##STR101## 9.1 m, 3H, CH₂ CH₃.

I.r. (cm⁻¹): 3400, OH, CO₂ H; ##STR102## CO₂ H.

Mass Spec. Meas. mass, M⁺, 475.3046; calc. mass, M⁺, 475.3046.

Compound 49

NMR (CDCl₃, 60 MHz)τ: 2.68 brs, 5H, --C₆ H₅ ; 4.02-5.04 brm, 2H, CH═CH; 5.34 brs, 2H, CH₂ Ph; 5.62-6.05 brm, 2H, N--CH₂ --; 6.18-6.44 brm, 6.35 s, 5H, N--CH₂, --CO₂ CH₃ ; 7.50-9.30 brm, 8.82 s, 25H.

I.r. (cm⁻¹): 3550, --OH; ##STR103##

Mass Spec. Meas. mass, 487.3071; calc. mass, M⁺, 487.3046.

PHARMACOLOGICAL DATA Bronchodilation Activity

The compounds are examined for their ability to inhibit 5-hydroxytryptamine or histamine induced bronchoconstriction in the anaesthetised artificially respired guinea-pig (Konzett-Rossler preparation).

The ED₅₀ values (μg/kg, i.v.) for inhibition of bronchoconstriction for a variety of the triazolidine-3,5-diones are given in Table 7.

                  TABLE 7                                                          ______________________________________                                                       ED.sub.50                                                        Compound      μg/kg, i.v.                                                   ______________________________________                                         29            2.6                                                              31            37                                                               32            0.74                                                             33            2.6                                                              43            1.9                                                              21            3.4                                                              24            4.0                                                              ______________________________________                                    

Anti-platelet Aggregation Activity

1-(6'-ethoxycarbonyl-n-hexyl)-2-(3"-hydroxy-n-octyl)-4-phenyl-1,2,4-triazolidine-3,5-dione (21) inhibited collagen induced aggregation in human platelet rich plasma. 

What we claim is:
 1. A pharmaceutical composition useful for effecting bronchodilation in humans and animals which comprises a therapeutically effective amount of a compound of the formula: ##STR104## or a pharmaceutically acceptable salt thereof wherein n has a value of from 1 to 5;Y is --CH₂ CH₂ --or --CH═CH--; R₁ is hydrogen or alkyl of 1 to 6 carbon atoms; R₂ when taken alone is hydrogen; alkyl of 1 to 4 carbon atoms; or phenyl; R₃ is hydroxy; R₄ when taken alone is hydrogen; alkyl of 1 to 9 carbon atoms; cycloalkyl of 3 to 8 carbon atoms; phenyl; naphthyl; or alkyl of 1 to 6 carbon atoms substituted with phenyl, naphthyl or cycloalkyl of 3 to 8 carbon atoms; any of said phenyl rings and said naphthyl rings being unsubstituted or substituted with halo, trifluoromethyl, alkyl of 1 to 6 carbon atoms, hydroxy, alkoxy of 1 to 6 carbon atoms, phenylalkoxy wherein alkoxy contains from 1 to 6 carbon atoms or nitro; R₂ and R₄ taken together, together with the carbon atom to which they are joined, are cycloalkylidene of 5 to 8 carbon atoms; and R₅ is hydrogen, alkyl of 1 to 6 carbon atoms, cycloalkyl of 5 to 8 carbon atoms; phenyl, alkyl of 1 to 6 carbon atoms substituted with phenyl or cycloalkyl of 3 to 8 carbon atoms substituted with phenyl, said phenyl rings being unsubstituted or substituted with halo, trifluoromethyl, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms or nitro, in combination with a pharmaceutically acceptable carrier.
 2. A composition according to claim 1 wherein R₅ is alkyl of 1 to 6 carbon atoms, n is 3, R₂ is hydrogen or methyl and R₄ is hex-2-yl, hept-2-yl or n-heptyl.
 3. A composition according to claim 1 wherein R₅ is methyl, n is 3, R₂ is hydrogen or methyl and R₄ is hex-2-yl, hept-2-yl or n-heptyl.
 4. A composition according to claim 1 wherein R₅ is alkyl of 1 to 6 carbon atoms, n is 3, R₂ is hydrogen or methyl, R₃ is hydroxy and R₄ is ##STR105## wherein T is a carbon-carbon bond or an alkylene chain which is straight or branched with one or two methyl groups and which has a total of 1 to 6 carbon atoms; and r has a value of from 0 to
 3. 5. A composition according to claim 1 wherein R₅ is methyl, n is 3, R₂ is hydrogen or methyl, R₃ is hydroxy and R₄ is ##STR106## wherein T is a carbon-carbon bond or an alkylene chain which is straight or branched with one or two methyl groups and which has a total of 1 to 6 carbon atoms; and r has a value of from 0 to
 3. 6. A composition according to claim 1 wherein the compound is 1-(6-carbomethoxyhexyl)-2-(3,4-dimethyl-3-hydroxyoctyl)-4-methyl-1,2,4-triazolidine-3,5-dione.
 7. A composition according to claim 1 in oral administration form.
 8. A composition according to claim 1 in parenteral administration form.
 9. A method of effecting bronchodilation in humans and animals which comprises administering to a human or animal in need thereof a therapeutically effective amount of a compound of the formula: ##STR107## or a pharmaceutically acceptable salt thereof wherein n has a value of from 1 to 5;Y is --CH₂ CH₂ -- or --CH═CH--; R₁ is hydrogen or alkyl of 1 to 6 carbon atoms; R₂ when taken alone is hydrogen; alkyl of 1 to 4 carbon atoms; or phenyl; R₃ is hydroxy; R₄ when taken alone is hydrogen; alkyl of 1 to 9 carbon atoms; cycloalkyl of 3 to 8 carbon atoms; phenyl; naphthyl; or alkyl of 1 to 6 carbon atoms substituted with phenyl, naphthyl or cycloalkyl of 3 to 8 carbon atoms; any of said phenyl rings and said naphthyl rings being unsubstituted or substituted with halo, trifluoromethyl, alkyl of 1 to 6 carbon atoms, hydroxy, alkoxy of 1 to 6 carbon atoms, phenylalkoxy wherein alkoxy contains from 1 to 6 carbon atoms or nitro; R₂ and R₄ taken together, together with the carbon atom to which they are joined, are cycloalkylidene of 5 to 8 carbon atoms; and R₅ is hydrogen, alkyl of 1 to 6 carbon atoms, cycloalkyl of 5 to 8 carbon atoms; phenyl, alkyl of 1 to 6 carbon atoms substituted with phenyl or cycloalkyl of 3 to 8 carbon atoms substituted with phenyl, said phenyl rings being unsubstituted or substituted with halo, trifluoromethyl, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms or nitro, in combination with a pharmaceutically acceptable carrier.
 10. A method according to claim 9 wherein R₅ is alkyl of 1 to 6 carbon atoms, n is 3, R₂ is hydrogen or methyl and R₄ is hex-2-yl, hept-2-yl or n-heptyl.
 11. A method according to claim 9 wherein R₅ is methyl, n is 3, R₂ is hydrogen or methyl and R₄ is hex-2-yl, hept-2-yl or n-heptyl.
 12. A method according to claim 9 wherein R₅ is alkyl of 1 to 6 carbon atoms, n is 3, R₂ is hydrogen or methyl, R₃ is hydroxy and R₄ is ##STR108## wherein T is a carbon-carbon bond or an alkylene chain which is straight or branched with one or two methyl groups and which has a total of 1 to 6 carbon atoms; and r has a value of from 0 to
 3. 13. A method according to claim 9 wherein R₅ is methyl, n is 3, R₂ is hydrogen or methyl, R₃ is hydroxy and R₄ is ##STR109## wherein T is a carbon-carbon bond or an alkylene chain which is straight or branched with one or two methyl groups and which has a total of 1 to 6 carbon atoms; and r has a value of from 0 to
 3. 14. A method according to claim 9 wherein the compound is 1-(6-carbomethoxyhexyl)-2-(3,4-dimethyl-3-hydroxyoctyl)-4-methyl-1,2,4-triazolidine-3,5-dione.
 15. A method according to claim 9 wherein the administration is oral.
 16. A method according to claim 9 wherein the administration is parenteral. 